Methamphetamine induces cardiomyopathy by Sigmar1 inhibition-dependent impairment of mitochondrial dynamics and function
Open Access
- 17 November 2020
- journal article
- research article
- Published by Springer Nature in Communications Biology
- Vol. 3 (1) , 1-20
Abstract
Methamphetamine-associated cardiomyopathy is the leading cause of death linked with illicit drug use. Here we show that Sigmar1 is a therapeutic target for methamphetamine-associated cardiomyopathy and defined the molecular mechanisms using autopsy samples of human hearts, and a mouse model of “binge and crash” methamphetamine administration. Sigmar1 expression is significantly decreased in the hearts of human methamphetamine users and those of “binge and crash” methamphetamine-treated mice. The hearts of methamphetamine users also show signs of cardiomyopathy, including cellular injury, fibrosis, and enlargement of the heart. In addition, mice expose to “binge and crash” methamphetamine develop cardiac hypertrophy, fibrotic remodeling, and mitochondrial dysfunction leading to contractile dysfunction. Methamphetamine treatment inhibits Sigmar1, resulting in inactivation of the cAMP response element-binding protein (CREB), decreased expression of mitochondrial fission 1 protein (FIS1), and ultimately alteration of mitochondrial dynamics and function. Therefore, Sigmar1 is a viable therapeutic agent for protection against methamphetamine-associated cardiomyopathy.Keywords
Funding Information
- U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (HL122354, HL145753, HL145753-01S1)
- U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute
- U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute
- LSUHSC-S CCDS Finish Line Award and Feist Weiller Cancer Center IDEA Grant are intramural grants provided by LSUHSC-Shreveport
This publication has 72 references indexed in Scilit:
- Sigma-1 Receptor Chaperone at the ER-Mitochondrion Interface Mediates the Mitochondrion-ER-Nucleus Signaling for Cellular SurvivalPLOS ONE, 2013
- Report of methamphetamine use and cardiomyopathy in three patientsDARU Journal of Pharmaceutical Sciences, 2012
- The sigma receptor agonist SA4503 both attenuates and enhances the effects of methamphetamineDrug and Alcohol Dependence, 2011
- Return to the fetal gene programAnnals of the New York Academy of Sciences, 2010
- Oxidative stress contributes to methamphetamine-induced left ventricular dysfunctionCardiovascular Research, 2010
- Acute methamphetamine exposure inhibits cardiac contractile functionToxicology Letters, 2009
- A Comparison of Echocardiographic Findings in Young Adults With Cardiomyopathy: With and Without a History of Methamphetamine AbuseClinical Cardiology, 2009
- Degradation of cAMP-Responsive Element–Binding Protein by the Ubiquitin-Proteasome Pathway Contributes to Glucotoxicity in β-Cells and Human Pancreatic IsletsDiabetes, 2009
- Attenuation of methamphetamine-induced effects through the antagonism of sigma (σ) receptors: Evidence from in vivo and in vitro studiesEuropean Neuropsychopharmacology, 2008
- Acute myocardial infarction in young adults who abuse amphetaminesDrug and Alcohol Dependence, 2008